目的 初步明确秋菊丸化学成分，研究秋菊丸对慢性高尿酸血症（HUA）模型大鼠尿酸（UA）升高及肾脏损伤的治疗作用及机制。方法 借助超高效液相色谱串联四极杆静电场轨道阱质谱（UPLC-Q-Exactive Orbitrap MS）技术，初步鉴定秋菊丸的化学成分。48只雄性SD大鼠随机分成对照组、模型组、苯溴马隆（5.45 mg·kg^-1，阳性药）组和秋菊丸低、中、高剂量（1.31、2.62、5.24 g·kg^-1）组，除对照组外，通过ig腺嘌呤和乙胺丁醇制备大鼠慢性HUA模型，造模同时每天ig给药1次，连续28 d。使用全自动生化仪测定大鼠血清UA、肌酐（CRE）、尿素氮（BUN）水平；HE及Masson染色观察肾脏组织病理学变化；实时荧光定量PCR（qRT-PCR）法检测肾脏组织中葡萄糖转运蛋白9 （GLUT9）、有机阴离子转运体家族蛋白3 （OAT3）、ATP结合盒亚家族G成员2（ABCG2）、转化生长因子-β（TGF-β1）、SMAD蛋白3（Smad3）、α-平滑肌肌动蛋白（α-SMA）的mRNA水平。结果 秋菊丸中共鉴定出41个成分，包括黄酮类（9个）、有机酸类（5个）、生物碱类（3个）、苯丙素类（7个）、香豆素类（1个）、酚类（3个）、呋喃类（2个）、脂肪酰类（6个）、醌类（2个）、萜类（1个）、内酯类（1个）、脂肪酸类（1个）。给药28 d后，HE染色结果表明，与模型组比较，各给药组肾损伤的病理学改变明显恢复，减轻了肾小球萎缩、肾小管扩张、肾纤维化及肾间质炎性细胞浸润等病理改变，其中秋菊丸高剂量组及苯溴马隆组肾脏损伤最轻。与模型组比较，秋菊丸高剂量组的CRE、UA水平均显著降低（P＜0.01），各剂量组BUN水平有降低趋势，但无显著性差异；高、中剂量组肾组织中肾小管上皮细胞中胶原蛋白的含量显著降低（P＜0.05、0.01）；高剂量组GLUT9 mRNA表达量显著减少（P＜0.05、0.01），各剂量组OAT3、ABCG2的mRNA表达量均显著增加（P＜0.05、0.01）；中、高剂量α-SMA mRNA表达量显著减少（P＜0.05、0.01），高剂量组TGF-β1 mRNA表达量显著减少（P＜0.01），各给药组Smad3的mRNA表达量有减少趋势，但无显著性差异。结论 初步明确秋菊丸化成成分，秋菊丸具有增强UA代谢、减轻HUA所致肾脏损伤及肾纤维化的作用，其机制可能与调控GLUT9-OAT3尿酸转运体相关。

Objective To preliminarily clarify the chemical composition of Qiuju Wan, and to study the therapeutic effect and mechanism of Qiuju Wan on the elevation of uric acid (UA) and kidney damage in chronic hyperuricemia (HUA) model rats. Methods Ultra-performance liquid chromatography tandem quadrupole electrostatic field, orbital well mass spectrometry (UPLC-QExactive Orbitrap MS) technology was used to preliminarily identify the chemical composition of Qiuju Wan. Forty-eight SD rats (males) were randomly divided into controlgroup, model group, benzbromarone (5.45 mg·kg^-1), and QJW low, medium, high dose (1.31, 2.62, and 5.24 g·kg^-1) group. Except for control group, the rat chronic HUA model was prepared by adenine and ethambutol intragastrically, which was simultaneously given intragastrically once a day for consecutive 28 days. Biochemical parameters such as UA, creatinine (CRE) and urea nitrogen (BUN) were determined, and histopathological changes of kidney were observed by HE and Masson staining. Gene levels of GLUT9, OAT3, ABCG2, TGF-β1, Smad3 and α-SMA in kidney tissue were detected by qRT-PCR. Results A total of 41 components were identified in Qiuju Wan, including flavonoids (9), organic acids (5), alkaloids (3), phenylpropanoids (7), coumarins (1), phenols (3), furans (2), fatty acyls (6), quinones (2), terpenoids (1), lactones (1), and fatty acids (1). After 28 days of administration, HE staining results showed that compared with the model group, the pathological changes of renal damage in each treatment group significantly recovered, reducing pathological changes such as glomerular atrophy, renal tubular dilation, renal fibrosis, and interstitial inflammatory cell infiltration. Among them, the high-dose group of Qiuju Wan and the group of benzbromarone had the least renal damage. Compared with model group, the CRE and UA levels in the high-dose group of Qiuju Wan were significantly reduced (P < 0.01), and the BUN levels in each dose group showed a decreasing trend, but there was no significant difference. Compared with model group, the content of collagen in renal tubular epithelial cells in high and medium dose groups significantly decreased (P < 0.05, 0.01). Compared with model group, the expression level of GLUT9 mRNA was significantly reduced in the high-dose group (P < 0.05, 0.01), while the mRNA expression levels of OAT3 and ABCG2 were significantly increased in each dose group (P < 0.05, 0.01). Compared with model group, the α-SMA mRNA expression levels of medium and high-dose group were significantly reduced (P < 0.05, 0.01), while the TGF-β1 mRNA expression was significantly reduced (P < 0.01) in high-dose group. The mRNA expression levels of Smad3 in each treatment group showed a decreasing trend, but there was no significant difference. Conclusion Qiuju Wan can regulate uric acid transporters, thereby enhancing uric acid metabolism and alleviating kidney damage and renal fibrosis caused by high uric acid, and its mechanism may be related to regulation of GLUT9-OAT3 uric acid transporter.

R284.1；R285.5

国家中医药管理局古代经典名方目录定制（第二批民族医药专题GZY-KJS-2019-011）；天山英才项目（2022TSYCCX0021，2022TSYCLJ009）；中医药传承与创新“百千万”人才工程-青年岐黄学者